A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction

被引:124
作者
Xia, ZQ
Gray, JA
Compton-Toth, BA
Roth, BL
机构
[1] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA
关键词
D O I
10.1074/jbc.M301905200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The serotonin (5-hydroxytryptamine) 2A receptor (5-HT2A) is an important G protein-coupled receptor ( GPCR) that mediates the effects of hallucinogens and is the target of a number of commonly prescribed medications including atypical antipsychotics, antidepressants, and anxiolytics. The 5-HT2A receptor possesses a canonical Type I PDZ-binding domain (X-Ser/Thr-X-Phi) at the carboxyl terminus and has been predicted, but never demonstrated, to interact with PDZ domain-containing proteins. We discovered that PSD-95, a prototypic PDZ domain-containing protein, directly associates with the 5-HT2A receptor and regulates 5-HT2A receptor-mediated signaling and trafficking in HEK-293 cells. Co-immunoprecipitation studies revealed that the native 5-HT2A receptor, but not a mutant lacking the PDZ-binding domain, interacted directly with PSD-95. The association with PSD-95 enhanced 5-HT2A receptor-mediated signal transduction, a novel action of PSD-95 on GPCRs. The augmentation of 5-HT2A receptor signaling by PSD-95 was not accompanied by alteration in the kinetics of 5-HT2A receptor desensitization but was associated with the inhibition of agonist-induced 5-HT2A receptor internalization. Additional studies demonstrated that 5-HT2A receptor and PSD-95 were co-localized in clusters on the cell surface of HEK-293 cells. Taken together, the present work elucidates novel roles for PSD-95 in regulating the functional activity and intracellular trafficking of 5-HT2A receptors and possibly other GPCRs.
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页码:21901 / 21908
页数:8
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共 54 条
[21]  
GUAN XM, 1992, J BIOL CHEM, V267, P21995
[22]   The β2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange [J].
Hall, RA ;
Premont, RT ;
Chow, CW ;
Blitzer, JT ;
Pitcher, JA ;
Claing, A ;
Stoffel, RH ;
Barak, LS ;
Shenolikar, S ;
Weinman, EJ ;
Grinstein, S ;
Lefkowitz, RJ .
NATURE, 1998, 392 (6676) :626-630
[23]  
Harris BZ, 2001, J CELL SCI, V114, P3219
[24]   Regulation of opioid receptor trafficking and morphine tolerance by receptor oligornerization [J].
He, L ;
Fong, J ;
von Zastrow, M ;
Whistler, JL .
CELL, 2002, 108 (02) :271-282
[25]   G protein-coupled receptor kinase 5 regulates β1-adrenergic receptor association with PSD-95 [J].
Hu, LA ;
Chen, W ;
Premont, RT ;
Cong, M ;
Lefkowitz, RJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (02) :1607-1613
[26]   β1-adrenergic receptor association with PSD-95 -: Inhibition of receptor internalization and facilitation of β1-adrenergic receptor interaction with N-methyl-D-aspartate receptors [J].
Hu, LYA ;
Tang, YT ;
Miller, WE ;
Cong, M ;
Lau, AG ;
Lefkowitz, RJ ;
Hall, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (49) :38659-38666
[27]   PDZ domains: Structural modules for protein complex assembly [J].
Hung, AY ;
Sheng, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (08) :5699-5702
[28]   Binding of neuroligins to PSD-95 [J].
Irie, M ;
Hata, Y ;
Takeuchi, M ;
Ichtchenko, K ;
Toyoda, A ;
Hirao, K ;
Takai, Y ;
Rosahl, TW ;
Sudhof, TC .
SCIENCE, 1997, 277 (5331) :1511-1515
[29]   5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex:: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites [J].
Jakab, RL ;
Goldman-Rakic, PS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (02) :735-740
[30]   Polarized signaling: basolateral receptor localization in epithelial cells by PDZ-containing proteins [J].
Kim, SK .
CURRENT OPINION IN CELL BIOLOGY, 1997, 9 (06) :853-859